tbuckley/cabot-search huggingface dataset:
Abstract 6280: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and HER2 for the treatment of breast as well as gastric cancer
Authors: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang
Journal: Cancer Research (2022)

Abstract Trastuzumab executes anti-tumor efficacy mainly via antibody-dependent cell cytotoxicity (ADCC). However due to the fact that majority of the populations including patients with cancers carry a CD16A-158F allele which has low binding affinity to the Fc fragment of trastuzumab, response to trastuzumab treatment is hindered. Furthermore, overexpression of CD47 on cancer cells prevent macrophages from activation via Fc-FcγRIIa interaction due to the so called “Don’t eat me” signal. We therefore designed a bispecific mAb-trap designated as IMM2902. Extensive in vitro as well as in vivo characterization demonstrated that IMM2902 binds to both CD47 and HER2 with high affinity (KD = 5.8x10-10M for HER2; KD = 8.9x10-9M for CD47) and has stronger ADCC activity against NCI-N87 (EC50 = 0.054nM for IMM2902, v.s. 0.868nM for trastuzumab). In vivo efficacy studies in several xenograft tumor models revealed a robust anti-tumor activity as reflected by the complete elimination of established tumors in BT-474 breast cancer and NCI-N87 gastric xenograft models even at the dose as low as 3.5mg/kg. Interestingly, even in Herceptin-resistant breast tumor model, when administered at a dose of 10mg/kg, the established HCC-1954 tumors were also eliminated. Immunohistochemistry staining of the tumor tissues demonstrated an accelerated HER2 degradation which is highly correlated with tumor volume. IMM2902 has no impact on hemagglutination, nor does it have significant hemotoxicity following single as well as multiple administrations in non-human primate animals at different dosage. Our study suggests that IMM2902 has the potential to be an alternative promising treatment option for patients with her2-positive cancers refractory to trastuzumab treatment. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and HER2 for the treatment of breast as well as gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6280.
An optimized ionizable cationic lipid for brain tumor-targeted siRNA delivery and glioblastoma immunotherapy
Authors: Shuhan Liu, Ji Liu, Haisong Li, Kuirong Mao, Haorui Wang, Xiandi Meng, Jialiang Wang, Chenxi Wu, Hongmei Chen, Xin Wang, Xiuxiu Cong, Yue Hou, Ye Wang, Ming Wang, Yong-Guang Yang, Tianmeng Sun
Journal: Biomaterials (2022)
P855: SYNERGISTIC EFFICACY OF COMBINED SUMOYLATION AND PROTEASOME INHIBITION IN MULTIPLE MYELOMA
Authors: U. Keller, G. Heynen, F. Baumgartner, M. Heider, U. Patra, J. Braune, P. Mertins, S. Müller, F. Bassermann, J. Krönke, M. Wirth
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is a genetically and clinically heterogeneous neoplastic plasma cell disorder. Treatment regimens for MM include proteasome inhibitors (PIs) which are routinely combined with dexamethasone and chemotherapeutics or immunomodulatory drugs (IMiDs). While such regimens have resulted in significant improvement of disease control and survival, the development of drug resistance remains a major clinical problem. Relapsed/refractory MM (r/r MM) is associated with particularly poor prognosis. New therapeutic strategies to further improve the management of MM and to overcome drug resistance are therefore urgently needed. SUMOylation is a post-translational protein modification pathway closely related to ubiquitylation. Hyperactive SUMOylation (SUMO) signalling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. Aims: We sought to identify stress response mechanisms associated with adverse prognosis and PI resistance. The overall goal was to develop novel therapy combinations targeting molecular vulnerabilities associated with advanced and/or PI-resistant MM. Methods: RNA-sequencing, unbiased mass spectrometry-based proteomics and bioinformatics analyses were used to interrogate the biology and in particular stress response pathways in MM. Cell culture finding were informed with primary MM patient data from gene expression studies and and survival data from clinical trials. Novel drug combination treatments were tested in MM cell-based models in vitro, in MM xenograft models in vivo, and in primary MM patient samples. Results: Here, we found that r/r MM is characterized by a state of activated SUMOylation, a ubiquitin-related post-translational protein modification pathway. High expression of the SUMO E1 activating enzyme (SAE1/UBA2) was associated with poor overall survival. Induced resistance to the second generation PI carfilzomib (CFZ) enhanced SUMO pathway activity. Accordingly, CFZ-pretreated patients showed enhanced SUMO pathway activity in the MM compartment. Treatment of MM cell lines with subasumstat (also TAK-981), a novel small-molecule inhibitor targeting the SUMO E1 activating enzyme, showed synergistic treatment efficacy with CFZ in both PI-sensitive and PI-resistant MM cell lines irrespective of the TP53 state. Combination therapy was effective in two murine MM xenograft models, where in vivo growth was significantly inhibited, and in patient-derived primary MM cells in vitro. Mechanistically, combinatorial treatment of subasumstat and CFZ enhanced genotoxic and proteotoxic stress and apoptosis. Summary/Conclusion: Our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel and potent strategy for the treatment of patients with MM.
A multiparametric niche-like drug screening platform in acute myeloid leukemia
Authors: Reinaldo Dal Bello, Justine Pasanisi, Romane Joudinaud, Matthieu Duchmann, Bryann Pardieu, Paolo Ayaka, Giuseppe Di Feo, Gaetano Sodaro, Clémentine Chauvel, Rathana Kim, Loic Vasseur, Laureen Chat, Frank Ling, Kim Pacchiardi, Camille Vaganay, Jeannig Berrou, Chaima Benaksas, Nicolas Boissel, Thorsten Braun, Claude Preudhomme, Hervé Dombret, Emmanuel Raffoux, Nina Fenouille, Emmanuelle Clappier, Lionel Adès, Alexandre Puissant, Raphael Itzykson
Journal: Blood Cancer Journal (2022)

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.
PB1754: TELOMERE LENGTH IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: E. Vakonaki, P. Iordanis, M. Tzatzarakis, A. Alegkakis, M. Lourou, N. Katzilakis, A. Tsatsakis, E. Stiakaki
Journal: HemaSphere (2022)

Background: Acute Lymphoblastic Leukemia (ALL) is the most common neoplastic disease in childhood with an excellent prognosis, accounting for 80% of all childhood malignancies. In almost 90% of ALL cases, numerical chromosomal as well as structural abnormalities, resulting in disruption of the expression of genes involved in hematopoiesis can be detected. As a result cells proliferate uncontrollably, leading to a rapid cell aging. A marker of the cellular senescence is the shortening of the telomere length. Telomeres have a protective role from chromosome degradation, recombination and fusion. In each cell division a reduction of telomeres occurs, until the Hayflick limit is reached and the cell is led to apoptosis. Aims: The purpose of the study was the evaluation of cellular aging in children and adolescents with ALL, determined by the telomere length measurement, as well as the possible correlation with the response to treatment, the risk of relapse and ultimately the overall survival. Methods: A total of 38 children, adolescents and young adults with the diagnosis of ALL were included in the study. The age range was from 1.5 to 18 years old and 25 were males. Regarding the lineage type of ALL, 33 were diagnosed with B-cell ALL and the remaining with T-ALL. A bone marrow sample was obtained at diagnosis and when remission was achieved. In case of relapse (3 children) additional samples were obtained. The telomere length was determined by qPCR methodology. Results: The mean telomere length in the lymphoblast specimens obtained at diagnosis was 1.97 ± 0.9 Kb, while at the time of remission the mean length was higher (4.35 ± 1.75 Kb). Two of the patients showed longer telomere length in lymphoblasts compared to normal lymphocytes at remission. Four of the patients had no difference in the mean telomere length between diagnosis and remission and these are the only with disease relapse. In these patients samples were also collected at relapse and no difference in telomeres length was noted as well. Grouping the patients according to the type of ALL, patients with T-ALL presented longer telomere length compared to those with B-ALL (3.27 ± 1.22 Kb versus 2.48± 1.87 Kb, respectively). High-risk group patients had longer telomere lengths compared to the intermediate-risk counterpart (2.89 ± 1.24 Kb and 2.41 ± 2.05 Kb respectively). Finally, comparing the telomeres length based on the karyotype analysis, individuals with 46 chromosomes had median telomere length of 2.73 ± 1.75 Kb, which is longer than those with a karyotype with > 46 chromosomes (2.33±2.14). Summary/Conclusion: The decrease of the telomere length observed at diagnosis seems to be reversible and could be attributed to the uncontrolled lymphoblastic proliferation. The telomeres length measurement could be correlated with disease progression and serve as a useful biomarker of ALL disease.
A collagen plug with shape memory to seal iatrogenic fetal membrane defects after fetoscopic surgery
Authors: Rob T.C. Meuwese, Elly M.M. Versteeg, Joris van Drongelen, Daniëlle de Hoog, Debora Bouwhuis, Frank P.H.A. Vandenbussche, Toin H. van Kuppevelt, Willeke F. Daamen
Journal: Bioactive Materials (2022)

Iatrogenic preterm premature rupture of fetal membranes (iPPROM) after fetal surgery remains a strong trigger for premature birth. As fetal membrane defects do not heal spontaneously and amniotic fluid leakage and chorioamniotic membrane separation may occur, we developed a biocompatible, fetoscopically-applicable collagen plug with shape memory to prevent leakage. This plug expands directly upon employment and seals fetal membranes, hence preventing amniotic fluid leakage and potentially iPPROM. Lyophilized type I collagen plugs were given shape memory and crimped to fit through a fetoscopic cannula (Ø 3 mm). Expansion of the plug was examined in phosphate buffered saline (PBS). Its sealing capacity was studied ex vivo using human fetal membranes, and in situ in a porcine bladder model. The crimped plug with shape memory expanded and tripled in diameter within 1 min when placed into PBS, whereas a crimped plug without shape memory did not. In both human fetal membranes and porcine bladder, the plug expanded in the defect, secured itself and sealed the defect without membrane rupture. In conclusion, collagen plugs with shape memory are promising as medical device for rapid sealing of fetoscopic defects in fetal membranes at the endoscopic entry point.
PB1818: INFLUENCE OF BODY MASS INDEX ON THE OUTCOME IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Authors: A. Elazab, M. Denewer, M. Mabed
Journal: HemaSphere (2022)

Background: Previous studies have demonstrated an association between high body mass index (BMI) and acute myeloid leukemias (AML). However, the results remain controversial. Aims: The aim of our study was to assess the impact of BMI on the outcome in adult patients with newly diagnosed AML Methods: Our study enrolled 140 patients with AML diagnosed between 2015 and 2020. The data were collected from Oncology Center, Mansoura University (OCMU) electronic medical record (eMR). They are further classified according to BMI into patients with normal BMI (40 patients), overweight (42 patients) and obese patients (58 patients) Results: No significant association is found between BMI and laboratory studies including CBCs, LDH (95% confidence interval [CI], P=0.645) or blast percentages in bone marrow aspirates (95% CI, p=0.587). As regard Complete Remission (CR) rates after induction chemotherapy with 3 + 7 protocol (three days of anthracycline+ seven days of cytrabine), our study concluded that CR rates are higher in patients with normal BMI when compared to overweight and obese patients (95% CI, p=0.004). BMI does not significantly affect disease-free survival (DFS) (95% CI, p=0.408). However, Higher BMI is associated with decreased overall survival (OS) (95% CI, p=0.004). Summary/Conclusion: In the treatment of acute myeloid leukemia in adults, overweight and obesity were associated with decreased complete response rates. However, overweight and obesity dont have a significant impact on disease free survival. A larger, prospective randomized trial would be required to confirm these results.
PB1789: WT1, HMGA2, EVI1, BAALC AND PRAME MRNA LEVELS IN PATIENTS BLOOD SAMPLES WITH ACUTE LEUKEMIA
Authors: M. Stolyar, A. Gorbenko, I. Olkhovskiy, M. Mikhalev, V. Bakhtina, T. Kaporskaya, V. Lyskova
Journal: HemaSphere (2022)

Background: An increase in the level of mRNA expression of a number of embryonic activity genes in blood samples from patients with acute leukemia is known. Among them, mRNAs of the WT1, HGMA2, EVI1, BAALC, and PRAME genes are most frequently mentioned, but previous publications do not discuss the possible diagnostic value of individual combinations of activity of these genes. Aims: To determine the profile of mRNA expression of these genes in blood samples from patients with acute leukemia Methods: The study included anonymous venous blood samples from patients with acute leukemia, sent to the laboratory for molecular genetic studies. A total of 129 blood samples from patients with initially diagnosed acute leukemia were examined. As a comparison group, 64 samples of patients with an altered ratio of blood cells, but without oncohematological diseases, were used. Testing was carried out by multiplex PCR using kits developed in the Krasnoyarsk branch of the Federal State Budgetary Institution National Research Center for Hematology. Statistical calculations were performed in the R. Results: The results indicate a high heterogeneity of indicators, while the levels of individual mRNAs did not correlate with each other, as well as with the level of leukocytosis or the proportion of blast cells. Maximum diagnostic efficiency (AUC 0.958; P<0.001) with a sensitivity of 83% and a specificity of 97% for distinguishing between samples of patients with acute leukemia and the comparison group was observed in the total assessment changes two mRNA of WT1 and BAALC genes (Figure). Image:Summary/Conclusion: The high diagnostic efficiency of a routine PCR test for evaluating mRNA activity in acute leukemia suggests that it can be used at the initial stage of diagnosis, especially in the absence or low level of blast cells in the venous blood of patients. In addition, the analysis of the obtained data confirms the hypothesis of a possible independent prognostic role of individual transcriptome profiles. The work was financed within the framework of the state assignment No. АААА-А20-120021890168-5.
PB2040: INTERRELATION BETWEEN JAK2 V617F MUTATION AND THE INCIDENCE OF THROMBOTIC EVENTS IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS
Authors: D. Nikolova, A. Yordanov, V. Damyanova, A. Radinov
Journal: HemaSphere (2022)

Background: Thrombotic incidents are the major cause of death for patients with Philadelphia negative myeloproliferative neoplasms (MPNs). During years, several studies have investigated the role of JAK2 V617F mutation as a risk inferring factor for thrombotic complications, but with ambiguous and contradictory findings. Aims: Our study aims to clarify the role of JAK2 V617F mutation in MPN in a large cohort of Bulgarian patients with previous medical history of vascular incidents. Methods: 231 patients with a confirmed clinical diagnosis of various MPNs (essential thrombocytemia/ET, polycythemia vera/PV and primary myelofibrosis/PMF) were screened for the presence of V617F mutation in JAK2 gene by molecular-genetic testing. The data was interrelated to the previously collected history of thrombotic events of the patients. The results were statistically analyzed. Results: The overall prevalence of thrombotic complications in our patients’ group was 25,01%. Venous thromboembolism occurred in 15 patients (25.9%), while brain/myocardial/splenic infarctions in 74.1% (43 patients). In patients from different groups, thrombotic events were distributed as follows: 39% in PV, 23.4% in ET and 40.6% in PMF. JAK2 V617F was found more frequently in patients with manifested thrombotic incidents (67.2%). There was no statistically significant difference in hematocrit, thrombocyte and hemoglobin level between patients with/without thrombotic incidents in different diagnostic groups. Summary/Conclusion: Based on these findings, initial screening for the JAK2 mutation and careful monitoring for thrombotic events should be performed in patients with MPN.
P1583: EVALUATION OF THE KNOWLEDGE OF HEMATOLOGISTS ABOUT THE MANAGEMENT OF INFECTIOUS COMPLICATIONS IN HEMATOLOGIC PATIENTS
Authors: M. Guaraná, M. Nucci
Journal: HemaSphere (2022)

Background: Infection is a serious complication among patients with hematologic malignancies (HM) and in hematopoietic cell transplant (HCT) recipients. In most centers, the management of these complications is provided by the hematologist itself, thus demanding a knowledge of basic aspects of infection. Aims: To evaluate the level of knowledge about infectious complications by hematologists, and to identify possible gaps that could help to design educational activities. Methods: We invited clinicians to answer two questionnaires with 20 multiple-choice questions covering areas of the epidemiology, prophylaxis, diagnosis and treatment of infection in patients with HM and HCT. Basic sociodemographic data of hematologists were also collected. Results: We obtained 289 answers: 223 in survey 1 (febrile neutropenia) and 66 in survey 2 (infection in HCT). The median score was 5.0 in both surveys (range 0.5-9.0). In survey 1, the questions with the lowest number of correct answers were Q3 (7%), about cefepime dose and Q1 (9%) which asked about the epidemiologic link between the use of high-dose cytarabine and viridans streptococcal bacteremia. In survey 2, two questions about cytomegalovirus (CMV) infection had the lowest percentage of correct answers (Q4, 12% and Q11, 18%). Clinicians taking care of HCT recipients had higher scores compared with clinicians taking care of patients with HM only (median score of 5.0 and 4.5, p=0.01 in survey 1, and 6.0 and 4.5, p=0.001 in survey 2). In both surveys staff clinicians, residents and professors had similar scores. Summary/Conclusion: This is the first study in Brazil assessing the knowledge of haematologists about infectious complications. The low median score overall indicates an urgent need for continuous education. Such initiatives will eventually result in better patient care.
P1661: THROMBOPATHY IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND AUTOIMMUNE DISEASE
Authors: E. Garcia Perez, E. Garcia Arias-Salgado, P. Acuña Butta, E. Monzon Manzano, M. T. Alvarez Roman, M. Gutierrez Alvariño, M. I. Rivas Pollmar, M. Martin Salces, A. Dos Santos Ortas, N. V. Butta Coll, V. Jimenez Yuste
Journal: HemaSphere (2022)

Background: Many patients with myelodysplastic syndromes (MDS) have associated autoimmune diseases due to the presence of clonality. The presence of non specific antibodies in these patients can alter hemostasis. Aims: We aim to study if there were differences in hemostasis of patients with MDS, depending on the coexistence or not of an autoimmune disease (AD) employing global coagulation tests, and flow cytometry to evaluate platelet function. Methods: This is an observational and prospective study. We included 21 patients with MDS without any associated autoimmune disease and 15 patients with autoimmune disease (Table 1). 46 healthy controls were also recruited. The following studies were carried out: - Platelet ability to be activated was tested by flow cytometry in platelet rich plasma using TRAP and ADP to induce platelet activation, and PAC1 monoclonal antibody (mAb) to recognize activated fibrinogen receptor, and anti P- selectin and anti-CD63 mAbs to evaluate, respectively, release from alpha and dense granules. - Global assessment of clot formation by calibrated automated thrombinography (CAT) and rotational thromboelastometry (ROTEM®). Results: Platelets from MDS patients, with and without AD, showed less capacity of activation compared to the control group. Despite there were no significant differences between the groups of patients with MDS, platelets from patients without AD showed a clear decrease in their ability to be activated by TRAP and was almost absent in three of them. Kinetics of clot formation evaluated by ROTEM® showed that all MDS patients had a hypocoagulable profile. Moreover, thrombin generation was lower in patients with MDS compared to controls. We observed that in the group of patients with AD the peak of thrombin and the endogenous thrombin potential were much lower than in patients without AD (p<0.01). Accordingly, patients with AD presented a longer lag time and time to peak than patients without AD (p<0.05). Image:Summary/Conclusion: Our results suggested the presence of non-specific antibodies in plasma of patients with MDS and AD that impaired hemostasis resulting in a hypocoagulable profile.